Traumatic brain injury (TBI) is a leading cause of clinical mortality and morbidity and a major public health problem. Currently, there is no proven treatment for clinical TBI beyond the prevention of secondary insults;yet, evidence for rapid post-traumatic changes in multiple protein kinase and phosphatase enzymes is accumulating suggesting that therapeutic manipulations of protein phosphorylation status after TBI may represent an unexploited therapeutic target. Recent studies in our laboratories have unexpectedly shown dramatic and acute changes in protein kinase A (PKA) RIIb function after TBI in an adult murine model using controlled cortical impact (CCI) using hypothermia treatment. Although other serine/threonine protein kinases were also affected by hypothermia, the changes in PKA activation were more dramatic suggesting that PKA may be a key mechanism in hypothermia neuroprotection and a target for kinase manipulation after experimental TBI. To this end, we found that the activation of PKA activity with Rolipram, (a type IV phosphodiesterase inhibitor [PDE4] which increases cAMP levels and PKA activation) and reduced spatial memory deficits after TBI in adult rats. Based on these findings, we propose that enhancement of PKA activity;with low dose (15g/kg) daily rolipram, during the acute and chronic phases, following experimental TBI may be beneficial. We propose: 1) PKA activation by acute low dose (15g/kg) rolipram treatment alone may reduce behavioral morbidity after moderate and severe TBI;2) PKA activation by chronic low dose (15g/kg) rolipram treatment alone will reduce behavioral morbidity after moderate and severe TBI;3) PKA activation by continuous daily low dose (15g/kg) rolipram treatment alone will most effectively reduce behavioral but not structural morbidity after moderate and severe TBI;4) Type II PKA regulatory subunits will be most affected by both injury and low dose (15g/kg) rolipram treatment after moderate and severe TBI;5) PKA activation by low dose (15g/kg) rolipram treatment will inhibit calpain and ubiquitin-mediated proteolysis, preserving many important serine/threonine protein kinase levels after moderate and severe TBI;6) PKA activation by low dose (15g/kg) will be associated with not only the preservation of general kinase levels, but will normalize glutamate NMDA and AMPA receptor levels, distribution, and PKA and PKC-dependent phosphorylation status. 7) Lastly, that low dose (15g/kg) rolipram provides behavioral efficacy after both moderate and severe TBI primarily via the cAMP-PKA pathway. PUBLIC HEALTH RELEVANCE: This project will evaluate a promising therapy (drugs that increase cAMP) for the treatment of experimental traumatic brain injury (TBI). This class of drug is already in clinical use for other purposes, and may bridge the time between injury and when patients arrive at the hospital. The drug may also be useful in the rehabilitation period after brain injury has occurred. Currently, there is no known effective treatment that has been translated to clinical TBI care.